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1 Clinical Trial Details (PDF Generation Date :- Thu, 14 Jul :46:45 GMT) CTRI Number Last Modified On 06/11/2012 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2011/08/ [Registered on: 19/08/2011] - Trial Registered Prospectively No Interventional Vaccine Preventive Randomized, Parallel Group, Active Controlled Trial A STUDY TO EVALUATE THE IMMUNOGENICITY AND SAFETY OF BBILs TYPHOID Vi CAPSULAR POLYSACCHARIDE-TETANUS TOXOID PROTEIN CONJUGATE VACCINE VS REFERENCE VACCINE IN HEALTHY SUBJECTS. A PHASE III, RANDOMIZED, MULTICENTERIC, CONTROLLED STUDY TO EVALUATE THE IMMUNOGENICITY AND SAFETY OF BBILs TYPHOID Vi CAPSULAR POLYSACCHARIDE-TETANUS TOXOID PROTEIN CONJUGATE VACCINE VS REFERENCE VACCINE IN HEALTHY SUBJECTS. Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) Details Contact Person (Public Query) BBIL/CTP/04/2010 Designation Affiliation Protocol Number Details of Principal Investigator Dr Anit Singh Asst. Medical Director Phone Fax Designation Affiliation Bharat Biotech International Ltd Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal Hyderabad, Andhra Pradesh Hyderabad India anits@bharatbiotech.com Details Contact Person (Scientific Query) Dr Anit Singh Asst. Medical Director Phone Fax Designation Affiliation Bharat Biotech International Ltd Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal Hyderabad, Andhra Pradesh Hyderabad India anits@bharatbiotech.com Details Contact Person (Public Query) Dr Anit Singh Asst. Medical Director Bharat Biotech International Ltd Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal Hyderabad, Andhra Pradesh Hyderabad page 1 / 8

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Details of Ethics Committee India Phone Fax Source of Monetary or Material Support > Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal Hyderabad, Andhra Pradesh Type of Sponsor NIL List of Countries India of Principal Investigator Primary Sponsor Details Bharat Biotech International Ltd Bharat Biotech International Ltd Genome Valley, Shameerpet Mandal Hyderabad, Andhra Pradesh Pharmaceutical industry-indian NIL of Site Site Phone/Fax/ Dr Monjori Mitra Institute of Child Health Institute of Child, Health11Dr.Biresh Guha Street Kolkata WEST BENGAL Dr P Venugopal King George Hospital Department of pediatrics, KGH, Vishakapatnam Visakhapatnam DrBSudhaka Priya Children Hospital Dept of pediatrics Priya Children Hospital New P&T Colony,Patamata Krishna Dr Mukesh Gupta soumya Child Clinic soumya Child Clinic, Near Laxmi mandir Cinima, Tonk road Jaipur RAJASTHAN Dr J Bhuvaneshwar Rao Sri Srinivasa Children Hospital Sri Srinivasa Children Hospital, Pediatrics Chiluku Durgaya Street Nakala Road Krishna monjori.mitra@medclins earch.com venugopal_kgh@yahoo.com drbsudhakar@gmail.co m drmukeshgupta.pediatri cs@gmail.com jnvbrao@rediffmail.com of Committee Approval Status Date of Approval Is Independent Ethics Committee? Central Ethics Committee Approved 20/06/2011 Yes Institute of Child Health Approved 03/08/2011 No Institute of Preventive medicine Approved 07/05/2011 No page 2 / 8

3 Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Inclusion Criteria Institutional ethics committee,mahavir medical Research center Institutional Ethics Committee, King George Hospital Approved 29/08/2011 No Approved 09/04/2011 No KLE University Approved 22/09/2011 No Sanjeevini ethics committee Vishakapatnam Central Ethics Committee Status Approved 28/05/2011 Yes Approved 20/06/2011 Yes Date Approved/Obtained 09/08/2011 Health Type Healthy Human Volunteers Condition To prevent Typhoid Type Details Comparator Agent TYPBAR Typhoid Vi capsular polysaccharide vaccine (TYPBAR) administered as one dose of 0.5 ml in all age Reference groups by intramuscular route. Intervention TYPHOID TT Vaccine Typhoid Vi capsular polysaccharide-tt protein conjugate vaccine manufactured by Bharat Biotech international Limited, Hyderabad. Administered as one dose of 0.5 ml in all age Test groups by intramuscular route. Age From Age To Gender Details 6.00 Month(s) Year(s) Both Inclusion Criteria 1. Provide voluntary written and signed informed consent from volunteer or if minor from parent/legal guardian. 2. Healthy subjects in two cohorts aged 6 to 24 months, and 2-45 years. 3. Are not participating in or plan to participate in another research during the next three months & be available throughout study period. 4. Family does not plan to move during the study period, and housed not further that 50 Km away from the study site. Exclusion Criteria Details Exclusion Criteria Fever of any origin or infections more than 3 days within one month prior to screening or on the day of screening 2) Any confirmed or suspected immunosuppressive condition. 3) Any treatment with immunosuppressive or immunostimulant therapy 4) Use of any marketed or investigational or herbal medicine or non-registered drug or vaccine for typhoid. 5) Life threatening or serious cardiac (NYHA grade 3&4), respiratory, gastrointestinal, hepatic, renal, endocrine and systemic disorders. page 3 / 8

4 6) Have been vaccinated against typhoid fever or had exposure to typhoid fever within the last three years. Method of Generating Random Sequence Method of Concealment Blinding/Masking Stratified block randomization An Open list of random numbers Open Label Primary Outcome Outcome Timepoints The comparative assessment of the immunogenicity of the test vaccine (conjugate typhoid vaccine) versus the comparator (polysaccharide typhoid vaccine) by estimation of: 1. 4 fold Seroconversion rates in each treatment arm at 6 weeks post vaccination fold Seroconversion rate in Cohort-1(2 years) from base line to 6 weeks post vaccination. 3. Extent of rise of anti Vi IgG antibody from baseline values to 6 weeks post vaccination The comparative assessment of the immunogenicity of the test vaccine (conjugate typhoid vaccine) versus the comparator (polysaccharide typhoid vaccine) by estimation of: 1. 4 fold Seroconversion rates in each treatment arm at 6 weeks post vaccination fold Seroconversion rate in Cohort-1(2 years) from base line to 6 weeks post vaccination. 3. Extent of rise of anti Vi IgG antibody from baseline values to 6 weeks post vaccination Secondary Outcome Outcome Timepoints 1. Comparative assessment of safety and tolerability of the vaccine in all subjects up to 3 months post vaccination. 2. Based on the Geometric Mean Titers of the primary objectives 1& 2 the superiority of test over reference vaccine will be determined 3 months Target Sample Size Phase of Trial Phase 3 Date of First Enrollment (India) Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial (India) Publication Details Total Sample Size=981 Sample Size from India=981 12/09/2011 No Date Specified Years=1 Months=0 Days=0 Not Applicable Completed Cohort Age group Vaccine Groups Total TEST REFERENCE page 4 / 8

5 1?6 months to?2 years >2 years to?45 years Total 981 The null hypothesis for the study assumes that the mean seroconversion rate (i.e a 4 fold rise of anti- Vi IgG antibody titer from baseline ) in the test group (? T ) and the control group (? C ) are equal i.e? T =? C and the alternate hypothesis is that they are not equal i.e? T?? C. The proposed sample size has been calculated on the basis of information from previous studies where the conjugate vaccine has demonstrated a seroconversion rate of about 80%. Therefore assuming an effect size in seroconversion rates as 10%,? of 0.05 and 80% power and equal allocation rates in both arms, the number of evaluable subjects required per group would be 294. If we assume a 10% drop out rate- evaluable subjects per group would be required i.e a total of 327. The sample size has been calculated using the Statistical software version 6. In the group <2 years we propose to recruit 327. Total sample size proposed for the study would be 981. Cohort-1: 327 (subjects aged?6months to?2 years Open Labeled, single arm). Cohort-2: 654 (subjects aged >2 years to?45 years- Double Blinded, two arms with equal allocation ratio). Note-1: The comparator vaccine is a polysaccharide vaccine which has T-cell independent nature of immune response and is not effective below 2 years and hence not approved for use in this age group. Also we examine other vaccines which could be used as comparator vaccine in below 2 years age group. The other vaccines which could be given in the control arm of this group would be different in the various stratified age range based on the Expanded Program on Immunization (EPI)/Indian Academy of Pediatrics (IAP) vaccine schedule leading to complexity of the study design and also statistical analysis. Considering all these issues this group (Cohort-1) would be single arm, an open labeled study. page 5 / 8

6 Note-2: The number of the subjects in Cohort-2 enrolled would be more (~400 subjects) in <15 years age group and less (~254 subjects) in >15 years because the common age group of getting typhoid fever is 2-15 years. he Subjects will be randomly assigned to test vaccine or Reference vaccine group as per the codes generated by the computer program. A copy of computer generated randomization list of subject numbers will be maintained by study member located at the center. The blinding key or decoding list of randomization will be provided to statistician at the time of statistical analysis by Asian Clinical Trials, Hyderabad. Services such as generation of randomization list, labeling of vials, blinding and generation of decoding list or envelops will be provided by the Asian Clinical Trials, Hyderabad. To evaluate the Safety and Immunogenicity of Typhoid Vi capsular polysaccharide-tt protein conjugate vaccine Vs Reference vaccine in healthy subjects. The comparative assessment of the immunogenicity of the test vaccine (conjugate typhoid vaccine) versus the comparator (polysaccharide typhoid vaccine) by estimation of: 1. 4 fold Seroconversion rates in each treatment arm at 6 weeks post vaccination fold Seroconversion rate in Cohort-1(<2 years) from base line to 6 weeks post vaccination. 3. Extent of rise of anti Vi IgG antibody from baseline values to 6 weeks post vaccination. 1. Comparative assessment of safety and tolerability of the vaccine in all subjects up to 3 months post vaccination. 2. Based on the Geometric Mean Titers of the primary objectives 1& 2 the superiority of test over reference vaccine will be determined. Typhoid fever is a very common and serious disease in developing countries like India. Salmonella typhi, the bacteria responsible to typhoid fever has become resistant to various antibiotics with raising concern. Methods to control typhoid fever, such as sanitary water and food supply alone with effective sewage treatment are not likely to be available in these countries in near future. page 6 / 8

7 The use of effective and safe vaccine especially in children could lessen the incidence of disease in endemic areas. The currently licensed vaccines have various limitations 1) Most of these vaccines have a efficacy of only 70 %, 2) Orally administered attenuated Ty21a requires at least three doses and has a low rate of efficacy in area with a high incidence of typhoid fever and its efficacy has not been demonstrated in children. 3) Parenterally administered vaccines are an age dependent serum antibody response and reinjection did not elicit a booster response (T-cell independent). To overcome the above limitations Vi polysaccharide has been conjugated with tetanus toxoid protein, this conjugation technique has been developed by Bharat Biotech. The new vaccine has a higher immunogenicity response and is T-cell dependent. All previous typhoid conjugate vaccines clinical studies have shown that the efficacy and immunogenicity of Typhoid conjugate 8, 9, 10. vaccine are higher than Vi polysaccharide vaccine alone This vaccine has already undergone the safety, immunogenicity and dose ranging studies in children 2 to 17 years in Phase II. The results suggest that the vaccine was absolutely safe, potent to produce an immune response to protect against Typhoid. The vaccine is efficacious to induce antibody titers required to protect for Typhoid disease and also superior to already registered commercially available Vi Capsular Polysaccharide vaccine. The single dose of 25?g/0.5mL Typhoid-TT conjugate vaccine showed adequate immune response, when compared to two doses of 25?g/ 0.5mL and two doses of 15?g/0.5mL dose of vaccine response and there is no significant difference between the groups. Hence the current study is to be undertaken to demonstrate the Immunogenicity and Safety of the new conjugate vaccine in the dosage of 25?g/0.5mL as single dose to diverse healthy population of age?6 months to?2 yrs, and? 2yrs to? 45 yrs. Data analysis will be performed by Indian Statistical Institute, Hyderabad / Medclin Research Kolkata. The data from various trial centers would be collected by representatives of Bharat Biotech after reviewing it at the site. The pre-vaccination geometric mean antibody (anti Vi anti IgG) titer at baseline will be compared with the 6 weeks post vaccination titers for detecting any statistically significant differences. The level of significance for the GMT analysis in both the arm will be considered as p<0.05 and the 95% CI for GMT. The mean of pre as well as post immunization antibody levels will be compared between two groups by Kruskal Wallis test. Repeated measure antibody levels in each group will be compared with the respective mean pre-immunization antibody levels by Friedman s ANOVA test. The mean seroconversion rate in each group will be calculated and between group comparisons will be done using Chi Square test or Fisher s exact test. The 95% CI will also be computed and values of p<0.05 will be considered statistically significant. page 7 / 8

8 Powered by TCPDF ( REF/2011/08/ The safety data will be described as the percentage of subjects presenting with each of the local and systemic reactions and comparisons will be made between the two groups using chi-square test or Fisher s exact tests. The 95% CI will also be computed and values of p<0.05 will be considered statistically significant. page 8 / 8